CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses

Marc Scherlinger (), Hao Li, Wenliang Pan, Wei Li, Kohei Karino, Theodoros Vichos, Afroditi Boulougoura, Nobuya Yoshida, Maria G. Tsokos and George C. Tsokos ()
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Marc Scherlinger: Beth Israel Deaconess Medical Center
Hao Li: Beth Israel Deaconess Medical Center
Wenliang Pan: Beth Israel Deaconess Medical Center
Wei Li: Beth Israel Deaconess Medical Center
Kohei Karino: Beth Israel Deaconess Medical Center
Theodoros Vichos: Beth Israel Deaconess Medical Center
Afroditi Boulougoura: Beth Israel Deaconess Medical Center
Nobuya Yoshida: Beth Israel Deaconess Medical Center
Maria G. Tsokos: Beth Israel Deaconess Medical Center
George C. Tsokos: Beth Israel Deaconess Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (Tfh) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the Tfh-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human Tfh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in Tfh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity.

Date: 2024
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DOI: 10.1038/s41467-024-45080-x

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